Epistasis in Steroidogenic Genes in the Prediction of Alzheimer's Disease

类固醇生成基因的上位性在阿尔茨海默病的预测中的作用

• 批准号: 8598792
• 负责人: Craig S Atwood
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598792
• 关键词: Activities of Daily Living; Address; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Andropause; Automobile Driving; Bilateral oophorectomy; Blood Circulation; Brain; Castration; Cerebrospinal Fluid; Chemicals; Cholesterol; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Conjugated Equine Estrogens; Controlled Study; Data; Dementia; Development; Diagnosis; Diagnostic Procedure; Diagnostic tests; Disease; Dysplasia; Endocrine; Estradiol; Estrogens; Family; Family member; Female; Follicle Stimulating Hormone; Gender; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genotype; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Health; Hippocampus (Brain); Hormones; In Vitro; Individual; Intervention Studies; Legal patent; Linkage Disequilibrium; Logistic Regressions; Luteinizing Hormone; MRI Scans; Marketing; Measures; Menopause; Nerve Degeneration; Neurologic; Neuropsychological Tests; Neurosecretory Systems; Pathway interactions; Patients; Performance; Peripheral; Physicians; Physiological; Pilot Projects; Plasma; Platelet Factor 4; Play; Positron-Emission Tomography; Postmenopause; Pregnenolone; Premenopause; Prevalence; Production; Progesterone; Proteins; Recording of previous events; Reporting; Risk; Risk Factors; Role; Sample Size; Sampling; Serum; Single Nucleotide Polymorphism; Steroid biosynthesis; Steroids; Test Result; Testing; Testosterone; Therapeutic; Time; Trauma; Uncontrolled Study; Veterans; Wisconsin; Woman; Women' s Health; age related; brain circulation; case control; gene interaction; genetic variant; genome wide association study; gonad function; in vivo; insight; male; member; men; mind control; neuronal transport; neurosteroids; outcome forecast; prognostic; public health relevance; research study; senescence; sex; tool

DESCRIPTION (provided by applicant): Evidence supporting sex steroids as being essential for normal cognitive health includes: 1) 12 studies demonstrating improvements in cognitive performance of cognitively healthy postmenopausal women taking 17¿-estradiol (E2), the major female estrogen, 2) improvements in cognition in subjects treated with physiologically relevant sex steroids: women treated with E2 (3 controlled/1 uncontrolled studies) and men treated with testosterone (T; 2 controlled studies), 3) the abrupt cognitive deficits observed in premenopausal women following 'chemical castration', deficits that are reversible with simultaneous administration of E2, 4) the increased risk of dementia in premenopausal women who have had a bilateral oophorectomy, 5) the increased prevalence of cognitive disease in women, which correlates with the abrupt earlier loss of gonadal function, 6) the elevated concentration of E2 in the brain compared to the circulation, and 7) the negative correlation between serum sex steroids, but positive correlation between serum gonadotropins, in women and men with AD. The above findings should NOT be confused with the widely reported Women's Health Initiative study which found a negative consequence of using UNPHYSIOLOGICAL conjugated equine estrogens. The above data indicate that the decline in circulating physiological sex steroids at menopause and during andropause would greatly impact brain functioning, and that those individuals with a higher synthetic capacity post-menopause and during andropause would be more likely to be spared the senescent changes induced by low sex steroid concentrations. We therefore hypothesize that those individuals with a lower neurosteroid synthetic capacity are more likely to develop AD, while those with a higher neurosteroid synthetic capacity will be spared longer the neurodegeneration induced by the age-related loss of peripheral sex steroids. Importantly, APOE ?4, the major risk factor for AD, and ABCA7, recently associated with AD from GWAS, alter the neuronal transport of cholesterol, the precursor from which all sex steroids are synthesized. Our preliminary studies have assessed sex steroid synthetic capacity by examining single nucleotide polymorphisms (SNPs) in genes of steroidogenic pathway family members (SPFMs) that regulate sex steroid synthesis. Identification of those genetic variations in members of the SPFM that cumulatively lower normal pathway function, i.e. that result in lower sex steroid synthesis are expected to associate with cognitive deficits. In this respect, we have found that gene-gene interactions between any 2 of APOE ¿4, lhcgr2 and fsh1 together with female gender significantly increases the risk of developing AD to >90%. This data is very promising, but to date we have analyzed only 240 case-control samples. This grant therefore aims to perform genotype and hormone analyses in a larger sample size to gain greater confidence that these interactions are important predictors of AD. To this end, in Specific Aim 1 we will genotype a further 2760 age- and sex- matched case-control samples and use analytic tools (logistic regression, multi-dimensionality reduction and recursive partitioning) to identify well supported gene-gene interactions that predict AD. In Specific Aim 2, we will measure 1) the concentrations of luteinizing hormone, follicle-stimulating hormone, E2, pregnenolone (P5), progesterone (P4) and T in matched plasma, CSF and hippocampus from 200 AD and age-matched control brains. This data will be analyzed to determine if plasma, CSF and brain concentrations of sex steroids are lower in AD, the relationship between plasma, CSF and brain sex steroids, and together with Specific Aim 1 genotyping data, if specific gene-gene interactions associated with AD are predictive of plasma, CSF and brain sex steroid concentrations. These experiments will determine that genetic variants in SPFMs regulate circulating and brain sex steroid synthesis and predict AD. Successful completion of these studies would enable the development of prognostic and diagnostic tests for AD, and provide insights into the neuroendocrine mechanisms of AD.

描述（由申请人提供）： 支持性类固醇对于正常认知健康至关重要的证据包括：1) 12 项研究表明，认知健康的绝经后女性服用 17¿-雌二醇 (E2)（主要的女性雌激素）可改善其认知表现，2) 使用生理相关性类固醇治疗的受试者的认知能力得到改善：接受 E2 治疗的女性（3 项对照研究/1 项非对照研究）和接受睾酮治疗的男性 （T；2 项对照研究），3）绝经前妇女在“化学阉割”后观察到的突然认知缺陷，这种缺陷可通过同时给予 E2 来逆转，4）接受双侧卵巢切除术的绝经前妇女患痴呆症的风险增加，5）女性认知疾病患病率增加，这与性腺早期突然丧失相关 功能，6）与循环相比，大脑中 E2 浓度升高，7）在患有 AD 的女性和男性中，血清性类固醇之间呈负相关，但血清促性腺激素之间呈正相关。上述发现不应与广泛报道的妇女健康倡议研究相混淆，该研究发现使用不符合生理学的结合马雌激素会产生负面后果。 上述数据表明，更年期和男性更年期循环生理性类固醇的下降将极大地影响大脑功能，而那些绝经后和男性更年期合成能力较高的个体更有可能免受低性类固醇浓度引起的衰老变化。因此，我们假设那些神经类固醇合成能力较低的人更有可能患 AD，而神经类固醇合成能力较高的人将更长时间地避免因年龄相关的外周性类固醇丧失而引起的神经退行性变。重要的是，APOE β4（AD 的主要危险因素）和 ABCA7（最近从 GWAS 中发现与 AD 相关）改变了胆固醇的神经元转运，而胆固醇是合成所有性类固醇的前体。 我们的初步研究通过检查调节性类固醇合成的类固醇生成途径家族成员 (SPFM) 基因中的单核苷酸多态性 (SNP) 来评估性类固醇的合成能力。 SPFM 成员中那些逐渐降低正常通路功能（即导致性类固醇合成降低）的遗传变异的鉴定预计与认知缺陷相关。在这方面，我们发现 APOE ¿4、lhcgr2 和 fsh1 中任意 2 个之间的基因-基因相互作用与女性性别一起显着增加患 AD 的风险至 >90%。这个数据非常有希望，但迄今为止我们只分析了 240 个病例对照样本。因此，这项资助的目的是在更大的样本量中进行基因型和激素分析，以增强人们对这些相互作用是 AD 的重要预测因素的信心。为此，在具体目标 1 中，我们将对另外 2760 个年龄和性别匹配的病例对照样本进行基因分型，并使用分析工具（逻辑回归、多维约简和递归分区）来识别预测 AD 的良好支持的基因-基因相互作用。在具体目标 2 中，我们将测量 1) 200 AD 和年龄匹配对照大脑的匹配血浆、脑脊液和海马中黄体生成素、卵泡刺激素、E2、孕烯醇酮 (P5)、黄体酮 (P4) 和 T 的浓度。将分析这些数据以确定 AD 中血浆、脑脊液和大脑性类固醇浓度是否较低，血浆、脑脊液和大脑性类固醇之间的关系，并与特定目标 1 基因分型数据一起确定与 AD 相关的特定基因-基因相互作用是否可以预测血浆、脑脊液和大脑性类固醇浓度。 这些实验将确定 SPFM 中的遗传变异调节循环和大脑性类固醇合成并预测 AD。这些研究的成功完成将有助于开发 AD 的预后和诊断测试，并为 AD 的神经内分泌机制提供见解。